cardiovascular risk updates cardiovascular risk updates usphs scientific and training symposium –...

Cardiovascular Risk UpdatesCardiovascular Risk UpdatesUSPHS Scientific and Training Symposium – Pharmacy Category

May 25th, 2010

LCDR Ryan Schupbach, Pharm.D., BCPS, CACP, NCPSLCDR Ryan Schupbach, Pharm.D., BCPS, CACP, NCPSClinical Pharmacy Director & PGY1 Residency DirectorClinical Pharmacy Director & PGY1 Residency Director

PHS Claremore Indian HospitalPHS Claremore Indian HospitalClinical Assistant Professor, University of Oklahoma College of Clinical Assistant Professor, University of Oklahoma College of

PharmacyPharmacy

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Objectives

• Identify novel cardiovascular biomarkers that correlate with enhanced cardiovascular risk

• Review contemporary literature likely to impact future cardiovascular guidelines

• Analyze new therapeutic approaches aimed at reducing cardiovascular morbidity and mortality

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Overview• Lipid/Lipoprotein review

• Review of NCEP ATP III* guideline targets

• Current shortfalls in CV risk assessment

• Recent studies of interest– INTERHEART– Emerging Risk Factors Collaboration– JUPITER

• Predictions??

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*Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert panel on detection , evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III)

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Lipid Component Review

• Lipid Composition– Cholesterol– Triglycerides (TGY)– Phospholipids

• Complexed with proteins to form “Lipoproteins”– Oil and water don’t mix!– Transport cholesterol &

TGY’s throughout the body – LDL, VLDL, HDL, etc.

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Major Lipoproteins

• LDL-c

• HDL-c

• VLDL-c– (i.e., TGY/5)

• IDL-c

• Chylomicrons

6Adapted from Pharmacotherapy – A Pathophysiological Approach 7 th edition. Dipiro et al. (McGraw – Hill, 2008).

Lipoproteins

LDL, VLDL, IDL– Transport cholesterol in aqeuous media– All contain an apolipoprotein B subtype (ApoB)– Collectively represent the “atherogenic” components

HDL – Promotes reverse cholesterol transport from cells in

the vessel wall to the liver for disposal– Contain “atheroprotective” apolipoprotein A1 (ApoA1)

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Lipoproteins in atherosclerosis

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CVDProgression

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NCEP ATP IIIReleased: 2001

NCEP ATP III Guidelines

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“LDL is the major atherogenic lipoprotein and has long been identified by NCEP as the primary target of cholesterol-lowering therapy”

“This focus on LDL has been strongly validated by recent clinical trials, which showthe efficacy of LDL-lowering therapy for reducing risk for CHD”

NCEP ATP III Guidelines

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CV biomarker shortfalls

• “Half of all myocardial infarctions and strokes occur despite apparently healthy men and women with LDL levels below currently recommended thresholds for treatment”1

• “Even with adequate LDL lowering, many patients on statin therapy have significant CVD risk”2

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1. Ridker PM, et al. Reduction in C-reactive protein and LDL cholesterol and CV events after initiation of rosuvastatin: a propective study of the JUPITER trial. Lancet. 2009:373: 1175-82.

2. Brunzell JD, et al. Lipoprotein management in patients with cardiometabolic risk. Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008; 31:811-22.

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Brunzell JD, et al. Lipoprotein management in patients with cardiometabolic risk. Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008; 31:811-22. 16

Emerging Risk Factors – ATP III excerpt

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Ideal new biomarker characteristics

• Can the biomarker be easily, precisely, and cost-effectively measured in a clinical setting?

• Are there available treatment strategies to positively alter the biomarker?

• Are the treatment strategies effective in reducing cardiovascular events?

18Brunzell JD, et al. Lipoprotein management in patients with cardiometabolic risk. Consensus statement for the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008; 31: 811-22.

New Cholesterol/CVD Biomarkers?• Non-HDL cholesterol• Apolipoproteins (Apo)

– Apolipoprotein A1 (ApoA1)– Apolipoprotein B (ApoB)– Apolipoprotein B/A1 ratio

• C-reactive Protein (CRP)• LDL particle size• Lipoprotein (a)• Lipoprotein-Associated Phospholipase A2

• Homocysteine

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Non-HDL Cholesterol

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Reasons non-HDL may be better than LDL

• non-HDL includes VLDL/TGY’s in risk equation– both LDL and TGY’s included

• Hypertriglyceridemia: – ↑ number of LDL particles (more atherogenic)– ↓ LDL size (small dense LDL are more atherogenic)– ↓ number of HDL particles (less anti-atherogenic)– ↓ HDL size (small dense HDL are less anti-atherogenic)

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“In other words, because non-HDL cholesterol incorporates the 2 atherogenic components, it appears overall to be a better predictor of CHD risk than LDL cholesterol alone”

Non-HDL trials vs. LDL• Other studies demonstrating non-HDL as a better predictor

of future CVD events– Cui Y, et al. Arch Intern Med. 2001 – Bittner V, et al. Circulation. 2002– Von Muellen D, et al. Am J Cardiol. 2003– Lu W, et al. Diabetes Care. 2003– Farwell W, et al. Am J Cardiol. 2005– Ridker P, et al. JAMA. 2005– Liu J, et al. Diabetes Care. 2005 – Pischon T, et al. Circulation. 2005– Rallidis L, et al. Atherosclerosis. 2005– Liu J, et al. Am J Cardiol. 2006– Everett B, et al. J Am Coll Cardiol. 2006

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Non-HDL cholesterol

• Advantages

– Already available in lipid panel• lack of expense

– Easy calculation

– May not require a fasting state*• Emerging Risk Factors & INTERHEART trial

– Non-HDL goals are ↑30mg/dL than LDL goal

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Apolipoproteins

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Apolipoprotein B (ApoB)

• Where’s the evidence?

– ApoB is suggested to more accurately represent the total burden of atherogenic particles

– LDL-c underestimates CV risk due to small, dense LDL particles

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Apolipoproteins

28Adapted from Pharmacotherapy – A Pathophysiological Approach 7 th edition. Dipiro et al. (McGraw – Hill, 2008).

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ApoB trials vs. LDL • Favor ApoB (vs. LDL-c)– Gotto A, et al. Circulation. 2000– Walldius G, et al. Lancet. 2001– Shai I, et al. Circulation. 2004– Ridker P, et al. JAMA. 2005– Pischon T, et al. Circulation. 2005– Everett B, et al. J Am Coll Cardiol. 2006– St. Pierre A, et al. Am J Cardiol. 2006– Hsia S, et al. Am J Cardiol. 2006– Ingelsson E, et al. JAMA. 2007– Benn M, et al. Arterioscler Thromb Vasc Biol. 2007

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ApoB advantages

• More trials favor CV risk predictability with ApoB than LDL, especially in statin-treated patients

• ApoB is accurate in a non-fasting state

• Practical way to estimate ApoB?• calculate non-HDL cholesterol

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LDL, non-HDL, and ApoB vs. CVDPost-hoc analysis of the TNT and IDEAL trials

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Post-hoc analysis of the TNT and IDEAL trials

Kastelein J, et al. Circulation 2008; 117:3002-9.

INTERHEART study - July 2008 -

35McQueen M, et al. Lipids, lipoproteins and apolipoproteins as risk marker s of myocardial infarction in 52 countries (The INTERHEART study). Lancet. 2008; 372:224-33.

INTERHEART results

36McQueen M, et al. Lipids, lipoproteins and apolipoproteins as risk marker s of myocardial infarction in 52 countries (The INTERHEART study). Lancet. 2008; 372:224-33.

ApoB

Non-HDL

HDL

ApoA1

INTERHEART results

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Authors interpretation: non-fasting ApoB/ApoA1 was superior to any cholesterol ratio for estimation of risk of acute MI in all ethnic groups, in both sexes, and at all ages, and should be introduced into worldwide clinical practice

ApoB/ApoA1

TC/HDL

The Emerging Risk Factors Collaboration - November 2009 -

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Emerging Risk Factors Collaboration - results

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Non-HDL

Apo B

Apo A1

HDL

Danesh J. The Emerging Risk Factor Collaboration. J Am Med Assoc. 2009;302:1993-2000.

Emerging Risk Factors Collaboration

• Authors conclusions– CHD risk assessment: use either lipids or apolipoproteins – Should hinge on practical considerations (cost, availability)– Fasting lipid values (vs. non-fasting) offer little value

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Hazard Ratio 95% CILDL 1.38 1.09-1.73non-HDL 1.42 1.06-1.91ApoB/ApoA1 1.49 1.39-1.60non-HDL/HDL 1.50 1.38-1.62

Danesh J. The Emerging Risk Factor Collaboration. J Am Med Assoc. 2009;302:1993-2000.

C-Reactive Protein (hsCRP)

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High sensitivity CRP

• Identified as a marker of underlying systemic inflammation

• Shown to independently predict future vascular events

• Can be reduced by statin therapy

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< 1 mg/L 1 to 3 mg/L > 3 mg/L

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NHS 2004

HPFUS 2004 EPIC-N 2005 Strong 2005 Kuopio 2005 FHS 2006

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CHS 2005 PIMA 2005

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hsCRP Adds Prognostic Information Beyond Traditional Risk Factors in All Major Cohorts Evaluated

Rosuvastatin 20 mg (N=8901)Rosuvastatin 20 mg (N=8901) MIMIStrokeStroke

UnstableUnstable AnginaAngina

CVD CVD DeathDeathCABG/CABG/PTCAPTCA

JUPITERJUPITERMulti-National Randomized Double Blind Placebo Controlled Trial of Multi-National Randomized Double Blind Placebo Controlled Trial of

Rosuvastatin in the Prevention of Cardiovascular EventsRosuvastatin in the Prevention of Cardiovascular EventsAmong Individuals With Low LDL and Elevated hsCRPAmong Individuals With Low LDL and Elevated hsCRP

4-week 4-week run-inrun-in

Ridker PM. Rationale and design of the JUPITER study. Circulation 2003;108:2292-97.

No Prior CVD or DMNo Prior CVD or DMMen Men >>50, Women 50, Women >>6060

LDL <130 mg/dL hsCRP >2 mg/L

JUPITERTrial Design

Placebo (N=8901)Placebo (N=8901)

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,

United Kingdom, Uruguay, United States, Venezuela

JUPITERPrimary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Placebo (251 / 8901)

Rosuvastatin (142 / 8901)

HR 0.56, 95% CI 0.46-0.69P < 0.00001

Number Needed to Treat (NNT5) = 25

- 44 %

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Number at Risk Follow-up (years)

RosuvastatinPlacebo

8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 1578,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

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We certainly know nothing certain!!– Non-HDL and ApoB > LDL in CV risk prediction– Non-HDL > ApoB (but likely interchangeable)– Ratios appears better than single biomarkers– Non-HDL/HDL = ApoB/ApoA1 ratio > TC/HDL– Consider treating CRP with LDL (or whichever!)

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Summary

LCDR Ryan Schupbach, Pharm.D., BCPS, CACP, NCPSLCDR Ryan Schupbach, Pharm.D., BCPS, CACP, NCPSPHS Claremore Indian HospitalPHS Claremore Indian Hospital

Ryan.Schupbach@ihs.govRyan.Schupbach@ihs.gov(918) 342-6455(918) 342-6455

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